Diabetes mellitus is a disorder of glucose regulation with accumulation of glucose in the blood. In normal individuals, insulin is secreted basally, usually in the range of 0.5 to 1.0 units per hour, and the levels are increased after a meal. Responsive to the rise in blood glucose levels following a meal, the pancreas secretes a bolus of insulin, which returns blood glucose to normal levels by stimulating the uptake of glucose into cells and signaling the liver to reduce glucose production. There are normally two phases of insulin release in response to a meal. The early phase (responsible for shutting down hepatic glucose production) is a spike of insulin release that occurs within 2-15 minutes of eating. The late phase release extends about 2 hours. Between meals the liver breaks down glycogen stores to provide glucose to the brain and other tissues.
Diabetes results in chronic hyperglycemia due to the inability or reduced ability of the pancreas to produce adequate amounts of insulin or due to the inability or reduced ability of cells to synthesize and/or release the insulin required. In diabetics, the effectiveness of the first-phase response is decreased or absent, leading to elevated postprandial glucose levels. Diabetes is a major public health problem affecting 285 million people across the world and this number is expected to be over 450 million by 2030 (Wild, et al., Diabetes Care, 27: 1047-1053 (2004). The malfunction of glucose regulation arises from 1) insufficient secretion of insulin due to autoimmune-mediated destruction of pancreatic f3-cells (type 1 diabetes) or 2) disorders of both insulin resistance and secretion (type 2 diabetes) (Pickup, et al., Diabetes Metab Res Rev, 24: 604-610 (2008); Stumvoll, et al. Lancet, 365:1333-1346 (2005); and Kahn, Diabetes 43:1066-1084 (1994).
Multiple subcutaneous insulin injections and regular monitoring of blood glucose levels are essential to sustain life for type 1 diabetic patients and some type 2 diabetic patients (Owens, et al., Lancet, 358:739-746 (2001)). However, such self-administration is painful and requires an indispensable commitment of patients. More importantly, this treatment, known as open-loop insulin delivery, does not maintain normoglycemia due to highly dynamic blood glucose concentrations (Jeandidier, et al., Adv Drug Deliv Rev, 35:179-198 (1999); Owens, et al., Nat Rev Drug Discov, 1:529-540 (2002)). Lack of tight control over glucose concentrations closer to the normal level accounts for many chronic complications such as limb amputation, blindness and kidney failure and often resulted in risks of fatal hypoglycemia (N Engl J Med., 329:977-986 (1993)). Therefore, a pancreas-like, synthetic closed-loop device able to continuously and intelligently release insulin in response to blood glucose levels is highly desirable (Kumareswaran, et al. Expert Rev Med Devices, 6:401-410 (2009); Ravaine, et al., J. Control Release, 132:2-11 (2008)).
A straightforward strategy is to integrate a glucose monitoring moiety and a sensor-triggered insulin releasing moiety into one system. To date, a number of glucose-responsive formulations and devices have been explored, mainly derived from three categories: 1) glucose oxidase (GOx) based enzymatic reaction-induced response systems; 2) lectin binding protein Concanavalin A (Con A) based response systems and 3) phenylboronic acid (PBA) based synthetic glucose-binding systems (Ravaine, et al., J. Control Release 132:2-11 (2008)).
A GOx based system is described in U.S. Pat. No. 4,364,385 to Lossef, et al., which is made of a compartment limited by a semipermeable, ionically charged membrane, containing glucose oxidase and catalase. U.S. Pat. No. 6,410,053 to Taylor discloses insulin immobilized in a dextran/concavalin A matrix, which can reversibly bind glucose and release insulin in response to changing glucose concentrations.
PBA is boronic acid containing a phenyl substituent and two hydroxyl groups attached to boron. PBA and its derivatives have the ability to form complexes with polyol molecules such as glucose, and fructose, in aqueous solution. PBA can form stable hydrogels with a polyol, such as poly(vinyl alcohol) (Hisamitsu, et al., Pharm Res 14:289-293 (1997)). The ability of PBA to bind polyols has been exploited in different ways to provide a glucose binding insulin delivery system. Hydrogels obtained from N-isopropylacrylamide (NIPAM) and PBA swelled and shrank according to the glucose concentration at pH 9. This system was modified to operate at physiological pH conditions by modifying the chemical structure of the receptor with an electron-withdrawing group on the phenyl ring. Matsumoto, et al., Biomolecules, 4(5):1410-6 (2003)). Other researchers have directly coupled a PBA moiety to insulin, to provide glucose binding insulin. For example, U.S. Publication No. 20030186846 by Hoeg-Johnson, et al., discloses an insulin delivery system made of insulin derivatives with a built in glucose sensor, such as an aryl boronate moiety.
These glucose insulin delivery systems have several limitations. The protein-involved platforms are not active for long periods due to denaturation under physiological conditions. The GOx based reaction needs additional dissolved oxygen. ConA exhibits significant cytotoxicity. These limit their implantable applications (Ravaine, et al., J. Control Release 132:2-11 (2008)). For PBA systems, the challenge remains to design devices that function in response to glucose at or near physiological pH. Moreover, formation of responsive biomaterials or relevant units requires synthetic polymerization (Ravaine, et al., J. Control Release 132:2-11 (2008)).
It is therefore an object of this invention to provide a PBA based insulin delivery system that is responsive to changing glucose concentrations at or near physiological pH.
It is also an object of the present invention to provide a method of making a PBA based glucose sensitive insulin delivery system that is responsive to glucose concentrations at or near physiological pH.
It is a further objection of the present invention to provide a method of controlling blood glucose levels in a patient in need thereof, by administering a PBA based insulin delivery system which responds to changing insulin concentrations at physiological pH.